Differential gene expression of chemokines in<i>KRAS</i>and<i>BRAF</i>mutated colorectal cell lines: Role of cytokines

Khan, Sajjad; Cameron, Silke; Blaschke, Martina; Moriconi, Federico; Naz, Naila; Amanzada, Ahmad; Ramadori, Giuliano; Malik, Ihtzaz Ahmed

doi:10.3748/wjg.v20.i11.2979

Cited by 22 publications

(20 citation statements)

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“…The results of ELISA assay verified the decrease of IL-8 and CXCL1 in CRC cells treated with sTLR4/MD-2 complex (Figure 4C). These results of pro-inflammatory and migration cytokines were consistent with previous studies [37, 38]. Since these pro-inflammatory and migration cytokines constituted tumor microenvironment of CRC to affect tumor progression [18], it was suggested in our study that sTLR4/MD-2 complex can inhibit tumor progress (Figure 5A) whereas sTLR4 or MD-2 alone could not inhibit tumor progress as effectively as sTLR4/MD-2 complex.…”

Section: Discussionsupporting

confidence: 92%

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS

et al. 2016

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Colorectal cancer (CRC) is aggressive and associated with TLR4-MD-2 signaling. Toll-like receptor 4 (TLR4) and myeloid differentiation protein 2 (MD-2) were highly expressed in human CRC. The soluble form of extracellular TLR4 domain (sTLR4) and MD-2 may have important roles in binding lipopolysaccharide (LPS). In this study, sTLR4 and MD-2 protein and prepared sTLR4/MD-2 complex were synthesized successfully to restrain LPS-TLR4/MD-2 activation by competing with cellular membrane TLR4 for binding LPS. The sTLR4/MD-2 complex can significantly attenuate LPS induced pro-inflammatory and migration cytokine production in vitro and in vivo, and inhibit the effect of LPS on the cell cycle, migration and invasion of human CRC cells in vitro. Administration of sTLR4/MD-2 complex protected mice from tumor both in xenograft and implantation metastasis model. The sTLR4/MD-2 complex treated mice had smaller tumor, less body weight loss and lower expression of inflammatory cytokines. Here, the azoxymethane/dextran sulfate sodium salt (AOM/DSS) murine model was used as an experimental platform to simulate the physiological and pathological processes of cancers associated with chronic intestinal inflammation. AOM/DSS-induced tumors were inhibited in mice treated by sTLR4/MD-2 complex. It is demonstrated in our study that sTLR4/MD-2 complex could inhibit CRC by competing with binding LPS, raising the complex's possibility of a new prevention agent against CRC.

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Section: Discussionsupporting

confidence: 92%

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS

et al. 2016

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“…A strength of our in vitro data is that the role of BRAF and KRAS mutation in the regulation of cytokine/chemokine secretion was studied in the same genetic and epigenetic background in Caco2 cells (MSS, CIMP negative, BRAF and KRAS wild type ). When cytokine/chemokine secretion was compared in BRAF and KRAS mutated CRC cell lines with different genetic backgrounds, the results were contradictory . However, our in vitro findings could also reflect the results of later analysis of the expression of CXCL10, CCL22 and TGFB1 in tumour specimens from CRC patients carrying oncogenic mutations in either BRAF or KRAS .…”

Section: Discussionmentioning

confidence: 64%

The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer

Ling

Lundberg

Eklöf

et al. 2015

The Journal of Pathology CR

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Giving strong prognostic information, T‐cell infiltration is on the verge of becoming an additional component in the routine clinical setting for classification of colorectal cancer (CRC). With a view to further improving the tools for prognostic evaluation, we have studied how Th1 lymphocyte infiltration correlates with prognosis not only by quantity, but also by subsite, within CRCs with different molecular characteristics (microsatellite instability, CpG island methylator phenotype status, and BRAF and KRAS mutational status). We evaluated the Th1 marker T‐bet by immunohistochemistry in 418 archival tumour tissue samples from patients who underwent surgical resection for CRC. We found that a high number of infiltrating Th1 lymphocytes is strongly associated with an improved prognosis in patients with CRC, irrespective of intratumoural subsite, and that both extent of infiltration and patient outcome differ according to molecular subgroup. In brief, microsatellite instability, CpG island methylator phenotype‐high and BRAF mutated tumours showed increased infiltration of Th1 lymphocytes, and the most pronounced prognostic effect of Th1 infiltration was found in these tumours. Interestingly, BRAF mutated tumours were found to be more highly infiltrated by Th1 lymphocytes than BRAF wild‐type tumours whereas the opposite was seen for KRAS mutated tumours. These differences could be explained at least partly by our finding that BRAF mutated, in contrast to KRAS mutated, CRC cell lines and tumour specimens expressed higher levels of the Th1‐attracting chemokine CXCL10, and reduced levels of CCL22 and TGFB1, stimulating Th2/Treg recruitment and polarisation. In conclusion, the strong prognostic importance of Th1 lymphocyte infiltration in CRC was found at all subsites evaluated, and it remained significant in multivariable analyses, indicating that T‐bet may be a valuable marker in the clinical setting. Our results also indicate that T‐bet is of value when analysed in molecular subgroups of CRC, allowing identification of patients with especially poor prognosis who are in need of extended treatment.

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“…Our observations that decrease CXCL1 secretion by SW620 cells inhibited their anchorage-independent and xenograft tumor growth are supported by similar findings in KRAS mutant LS174T CRC cells, whose malignant growth were inhibited by CXCL1 siRNA or neutralizing α-CXCL1 antibody [ 24 , 25 ]. Treatment of KRAS mutant DLD-1 CRC cells with KRAS siRNA resulted in suppression of KRAS mutant expression and a corresponding decrease in CXCL1 level [ 26 ]. Interestingly, colorectal tumors that developed due to chronic ulcerative colitis had a lower frequency of KRAS mutation [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts

et al. 2015

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BackgroundClinical therapy for metastatic colorectal cancer (CRC) remains limited, especially when the tumor harbors a KRAS mutation. This study aimed to identify prognostic biomarkers in CRC that are accessible for therapeutic inhibition.MethodsConditioned media from human CRC epithelial cells and myofibroblasts were screened by cytokine arrays for tumorigenic factors. The protein and mRNA expressions of these factors were determined by immunohistochemistry and gene microarrays in human CRC tissues. Prognostic biomarkers were determined by correlation of mRNA expression to overall survival in stage IV CRC patients. Inhibition of CXCL1 was performed with specific neutralizing antibody and lentiviral shRNAs. Malignant growth was assessed by soft agar growth assays and xenograft tumor growth in immunocompromised mice.ResultsCXCL1 was highly secreted by KRAS mutant human CRC cells and myofibroblasts in a complementary adaptive response to serum deprivation. Elevated CXCL1 level promoted anchorage-independent growth of murine fibroblasts and human CRC cells. Inhibition of CXCL1 by neutralizing antibody and specific shRNAs decreased CRC tumor growth. Highly elevated CXCL1 expression significantly correlated with decreased overall survival in stage IV CRC patients (hazard ratio 0.28; 95% CI 0.11–0.72).ConclusionsHigh CXCL1 expression is a poor prognostic biomarker in metastatic CRC. CXCL1 inhibition suppressed tumorigenic growth of KRAS mutant CRC cells.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0555-4) contains supplementary material, which is available to authorized users.

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Differential gene expression of chemokines inKRASandBRAFmutated colorectal cell lines: Role of cytokines

Cited by 22 publications

References 55 publications

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS

sTLR4/MD-2 complex inhibits colorectal cancer in vitro and in vivo by targeting LPS

The infiltration, and prognostic importance, of Th1 lymphocytes vary in molecular subgroups of colorectal cancer

The prognostic significance of CXCL1 hypersecretion by human colorectal cancer epithelia and myofibroblasts

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